AXL-initiated paracrine activation of pSTAT3 enhances mesenchymal and vasculogenic supportive features of tumor-associated macrophages

Chia Nung Hung; Meizhen Chen; Daniel T. DeArmond; Cheryl H.L. Chiu; Catherine A. Limboy; Xi Tan; Meena Kusi; Chih Wei Chou; Li Ling Lin; Zhao Zhang; Chiou Miin Wang; Chun Liang Chen; Kohzoh Mitsuya; Pawel A. Osmulski; Maria E. Gaczynska; Nameer B. Kirma; Ratna K. Vadlamudi; Don L. Gibbons; Steve Warner; Andrew J. Brenner; Daruka Mahadevan; Joel E. Michalek; Tim H.M. Huang; Josephine A. Taverna

doi:10.1016/j.celrep.2023.113067

AXL-initiated paracrine activation of pSTAT3 enhances mesenchymal and vasculogenic supportive features of tumor-associated macrophages

Chia Nung Hung, Meizhen Chen, Daniel T. DeArmond, Cheryl H.L. Chiu, Catherine A. Limboy, Xi Tan, Meena Kusi, Chih Wei Chou, Li Ling Lin, Zhao Zhang, Chiou Miin Wang, Chun Liang Chen, Kohzoh Mitsuya, Pawel A. Osmulski, Maria E. Gaczynska, Nameer B. Kirma, Ratna K. Vadlamudi, Don L. Gibbons, Steve Warner, Andrew J. BrennerDaruka Mahadevan, Joel E. Michalek, Tim H.M. Huang, Josephine A. Taverna

Research output: Contribution to journal › Article › peer-review

3 Scopus citations

Abstract

Tumor-associated macrophages (TAMs) are integral to the development of complex tumor microenvironments (TMEs) and can execute disparate cellular programs in response to extracellular cues. However, upstream signaling processes underpinning this phenotypic plasticity remain to be elucidated. Here, we report that concordant AXL-STAT3 signaling in TAMs is triggered by lung cancer cells or cancer-associated fibroblasts in the cytokine milieu. This paracrine action drives TAM differentiation toward a tumor-promoting “M2-like” phenotype with upregulation of CD163 and putative mesenchymal markers, contributing to TAM heterogeneity and diverse cellular functions. One of the upregulated markers, CD44, mediated by AXL-IL-11-pSTAT3 signaling cascade, enhances macrophage ability to interact with endothelial cells and facilitate formation of primitive vascular networks. We also found that AXL-STAT3 inhibition can impede the recruitment of TAMs in a xenograft mouse model, thereby suppressing tumor growth. These findings suggest the potential application of AXL-STAT3-related markers to quantitatively assess metastatic potential and inform therapeutic strategies in lung cancer.

Original language	English (US)
Article number	113067
Journal	Cell Reports
Volume	42
Issue number	9
DOIs	https://doi.org/10.1016/j.celrep.2023.113067
State	Published - Sep 26 2023

Keywords

AXL
CP: Cancer
CP: Immunology
CyTOF
Dubermatinib
Momelotinib
STAT3
tumor microenvironment
tumor-associated macrophage

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.celrep.2023.113067

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Hung, C. N., Chen, M., DeArmond, D. T., Chiu, C. H. L., Limboy, C. A., Tan, X., Kusi, M., Chou, C. W., Lin, L. L., Zhang, Z., Wang, C. M., Chen, C. L., Mitsuya, K., Osmulski, P. A., Gaczynska, M. E., Kirma, N. B., Vadlamudi, R. K., Gibbons, D. L., Warner, S., ... Taverna, J. A. (2023). AXL-initiated paracrine activation of pSTAT3 enhances mesenchymal and vasculogenic supportive features of tumor-associated macrophages. Cell Reports, 42(9), Article 113067. https://doi.org/10.1016/j.celrep.2023.113067

Hung, CN, Chen, M, DeArmond, DT, Chiu, CHL, Limboy, CA, Tan, X, Kusi, M, Chou, CW, Lin, LL, Zhang, Z, Wang, CM, Chen, CL, Mitsuya, K, Osmulski, PA , Gaczynska, ME , Kirma, NB , Vadlamudi, RK, Gibbons, DL, Warner, S, Brenner, AJ , Mahadevan, D , Michalek, JE , Huang, THM & Taverna, JA 2023, 'AXL-initiated paracrine activation of pSTAT3 enhances mesenchymal and vasculogenic supportive features of tumor-associated macrophages', Cell Reports, vol. 42, no. 9, 113067. https://doi.org/10.1016/j.celrep.2023.113067

@article{39f890ae31714fc5a706506d2a82de23,

title = "AXL-initiated paracrine activation of pSTAT3 enhances mesenchymal and vasculogenic supportive features of tumor-associated macrophages",

abstract = "Tumor-associated macrophages (TAMs) are integral to the development of complex tumor microenvironments (TMEs) and can execute disparate cellular programs in response to extracellular cues. However, upstream signaling processes underpinning this phenotypic plasticity remain to be elucidated. Here, we report that concordant AXL-STAT3 signaling in TAMs is triggered by lung cancer cells or cancer-associated fibroblasts in the cytokine milieu. This paracrine action drives TAM differentiation toward a tumor-promoting “M2-like” phenotype with upregulation of CD163 and putative mesenchymal markers, contributing to TAM heterogeneity and diverse cellular functions. One of the upregulated markers, CD44, mediated by AXL-IL-11-pSTAT3 signaling cascade, enhances macrophage ability to interact with endothelial cells and facilitate formation of primitive vascular networks. We also found that AXL-STAT3 inhibition can impede the recruitment of TAMs in a xenograft mouse model, thereby suppressing tumor growth. These findings suggest the potential application of AXL-STAT3-related markers to quantitatively assess metastatic potential and inform therapeutic strategies in lung cancer.",

keywords = "AXL, CP: Cancer, CP: Immunology, CyTOF, Dubermatinib, Momelotinib, STAT3, tumor microenvironment, tumor-associated macrophage",

author = "Hung, {Chia Nung} and Meizhen Chen and DeArmond, {Daniel T.} and Chiu, {Cheryl H.L.} and Limboy, {Catherine A.} and Xi Tan and Meena Kusi and Chou, {Chih Wei} and Lin, {Li Ling} and Zhao Zhang and Wang, {Chiou Miin} and Chen, {Chun Liang} and Kohzoh Mitsuya and Osmulski, {Pawel A.} and Gaczynska, {Maria E.} and Kirma, {Nameer B.} and Vadlamudi, {Ratna K.} and Gibbons, {Don L.} and Steve Warner and Brenner, {Andrew J.} and Daruka Mahadevan and Michalek, {Joel E.} and Huang, {Tim H.M.} and Taverna, {Josephine A.}",

note = "Publisher Copyright: {\textcopyright} 2023 The Authors",

year = "2023",

month = sep,

day = "26",

doi = "10.1016/j.celrep.2023.113067",

language = "English (US)",

volume = "42",

journal = "Cell Reports",

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T1 - AXL-initiated paracrine activation of pSTAT3 enhances mesenchymal and vasculogenic supportive features of tumor-associated macrophages

AU - Hung, Chia Nung

AU - Chen, Meizhen

AU - DeArmond, Daniel T.

AU - Chiu, Cheryl H.L.

AU - Limboy, Catherine A.

AU - Tan, Xi

AU - Kusi, Meena

AU - Chou, Chih Wei

AU - Lin, Li Ling

AU - Zhang, Zhao

AU - Wang, Chiou Miin

AU - Chen, Chun Liang

AU - Mitsuya, Kohzoh

AU - Osmulski, Pawel A.

AU - Gaczynska, Maria E.

AU - Kirma, Nameer B.

AU - Vadlamudi, Ratna K.

AU - Gibbons, Don L.

AU - Warner, Steve

AU - Brenner, Andrew J.

AU - Mahadevan, Daruka

AU - Michalek, Joel E.

AU - Huang, Tim H.M.

AU - Taverna, Josephine A.

PY - 2023/9/26

Y1 - 2023/9/26

N2 - Tumor-associated macrophages (TAMs) are integral to the development of complex tumor microenvironments (TMEs) and can execute disparate cellular programs in response to extracellular cues. However, upstream signaling processes underpinning this phenotypic plasticity remain to be elucidated. Here, we report that concordant AXL-STAT3 signaling in TAMs is triggered by lung cancer cells or cancer-associated fibroblasts in the cytokine milieu. This paracrine action drives TAM differentiation toward a tumor-promoting “M2-like” phenotype with upregulation of CD163 and putative mesenchymal markers, contributing to TAM heterogeneity and diverse cellular functions. One of the upregulated markers, CD44, mediated by AXL-IL-11-pSTAT3 signaling cascade, enhances macrophage ability to interact with endothelial cells and facilitate formation of primitive vascular networks. We also found that AXL-STAT3 inhibition can impede the recruitment of TAMs in a xenograft mouse model, thereby suppressing tumor growth. These findings suggest the potential application of AXL-STAT3-related markers to quantitatively assess metastatic potential and inform therapeutic strategies in lung cancer.

AB - Tumor-associated macrophages (TAMs) are integral to the development of complex tumor microenvironments (TMEs) and can execute disparate cellular programs in response to extracellular cues. However, upstream signaling processes underpinning this phenotypic plasticity remain to be elucidated. Here, we report that concordant AXL-STAT3 signaling in TAMs is triggered by lung cancer cells or cancer-associated fibroblasts in the cytokine milieu. This paracrine action drives TAM differentiation toward a tumor-promoting “M2-like” phenotype with upregulation of CD163 and putative mesenchymal markers, contributing to TAM heterogeneity and diverse cellular functions. One of the upregulated markers, CD44, mediated by AXL-IL-11-pSTAT3 signaling cascade, enhances macrophage ability to interact with endothelial cells and facilitate formation of primitive vascular networks. We also found that AXL-STAT3 inhibition can impede the recruitment of TAMs in a xenograft mouse model, thereby suppressing tumor growth. These findings suggest the potential application of AXL-STAT3-related markers to quantitatively assess metastatic potential and inform therapeutic strategies in lung cancer.

KW - AXL

KW - CP: Cancer

KW - CP: Immunology

KW - CyTOF

KW - Dubermatinib

KW - Momelotinib

KW - STAT3

KW - tumor microenvironment

KW - tumor-associated macrophage

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U2 - 10.1016/j.celrep.2023.113067

DO - 10.1016/j.celrep.2023.113067

M3 - Article

C2 - 37659081

AN - SCOPUS:85170030555

SN - 2211-1247

VL - 42

JO - Cell Reports

JF - Cell Reports

IS - 9

M1 - 113067

ER -

AXL-initiated paracrine activation of pSTAT3 enhances mesenchymal and vasculogenic supportive features of tumor-associated macrophages

Abstract

Keywords

ASJC Scopus subject areas

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